1. Technical Field of the Invention
The present invention relates to novel fumagalone compounds, as novel and useful industrial products. This invention also relates to their method of preparation and to their formulation into pharmaceutical compositions suited for administration in human or veterinary medicine, or formulated into cosmetic compositions.
2. Description of Background and/or Related and/or Prior Art
As is well known, angiogenesis is the formation of new blood vessels from existing vessels. Angiogenesis plays an important role in the development of the tissues of the embryo but hardly ever occurs in healthy adult tissues.
The development of new blood vessels may be observed in non-physiological conditions. This development can be beneficial, for example in the case of cicatrization. But its action is generally harmful: development of tumors, or accompanying chronic inflammatory diseases.
The role of angiogenesis is most evident in the case of tumors: it has been demonstrated that, in the growth phase, the development of new blood vessels was absolutely essential for tumors.
Although the link from development of a tumor and angiogenesis was suggested by Folkman more than thirty years ago (Folkman, J., New. Engl. J. Med., 1971, 285, 1182), it is only in the last ten years or so that the possibility of anti-tumor therapies based on control of angiogenesis has been widely accepted. At the present time, numerous anti-angiogenic molecules are under clinical investigation (Norrby, K., APMIS, 1997, 105, 417-437; Arbiser, J. L., J. Am. Acad. Dermatol., 1996, 34(3), 486-497; Fan, T-P. D., TIPS, 1995, 16, 57-66). As was shown recently (Boehm, T., Folkman, J. et al. Nature, 1997, 390, 404-407), an anti-tumor therapy based on control of angiogenesis is less likely to result in the appearance of resistance phenomena.
Angiogenesis is also associated with the pathological process of various inflammatory diseases. Accordingly, inhibition of angiogenesis can have implications for the treatment and prevention of these diseases. Thus, abnormal angiogenesis is involved in various diseases of an inflammatory nature.
Many groups of researchers have attempted to discover novel molecules capable of inhibiting angiogenesis, for example Taylor by using protamine (Taylor, S. et al., Nature, 1982, 297, 307) or the use of heparin in the presence of cortisone by Folkman (Folkman, J. et al., Science, 1983, 221, 719).
In dermatology, it is very widely accepted that a problem with control of angiogenesis is associated with a great many disorders: tumors, haemangiomas (excessive angiogenesis) (Creamer, D. et al., Br. J. Dermatol., 1997, 136 (6), 859-865; Jackson, J. R. et al. FASEB. J., 1997, 11(6), 457-465), ulcers (deficient angiogenesis).
To date, steroids have been used for the treatment of haemangiomas, and their efficacy is probably due to their anti-angiogenic activity.
It is also apparent that angiogenesis is receiving increased attention as a target for therapeutic intervention in other dermatologic disorders. This is evident at the clinical level, for example, from the design of studies focusing on angiogenesis (Gradishar, W. J. Invest New Drugs, 1997, 15(1), 49-59) and from the increasing number of reports, articles and publications referring to angiogenesis (Angiogenesis. Rep. Med. Chem., 1997, 32, 161-170; Angiogenesis. Rep. Med. Chem., 1992, 27, 139-148).
Finally, it should be noted that various classes of molecules with dermatological activity (retinoids, vitamin 1,25-di-OH-D-3) are now being examined for their potential role in angiogenesis (Eur J. Pharmacol., 1993, 249 (1), 113-116; Cancer Lett., 1995, 89 (1) 117-124).
In the field of angiogenesis, fumagillin and derivatives thereof occupy a special place: TNP-470 (AGM 1470) described in EP-0-357,061 and its successor, FR-118847 described in EP-0-386,667, are active in many models of angiogenesis and have a recognized anti-tumor activity (Logothetis, C. J., Clin Cancer Res., 2001 May; 7(5):1198-1203).
These compounds are described as having activity in inhibition of angiogenesis, suppression of cellular proliferation and immunosuppression.
These compounds are synthesized by conventional methods of hemisynthesis as described in EP-0-357,061 and EP-0-386,667 cited above.
Other derivatives of fumagillin, such as the 6-epifumagillols described in EP-0-387,650, also have applications in inhibition of angiogenesis, suppression of cellular proliferation and immunosuppression. Once again, they are synthesized by a hemisynthetic method.
The mode of action of these compounds remained unexplained until 1997, when a biological target, a methionine aminopeptidase: MetAP-2, was identified (Griffith, E. C. et al. Chem. Biol., 1997, 4(6), 461-471). The inhibitory activity of various derivatives of fumagillin on this enzyme displays good correlation with the anti-angiogenic effect.
The discovery of this enzyme permitted better targeting of research activity and synthesis of novel analogues of fumagillin having better biological activity while reducing their side-effects. In particular, the mode of action proposed by Griffith, Liu and Clardy (a; Liu, S. et al. Science, 1998, 282, 1324-1327. b; Griffith, E. C. et al. Proc. Natl. Acad. Sci. USA, 1998, 95, 15183-15188) for fumagillin and its analogues involves crucial interaction from the exocyclic epoxide of these molecules and a cobalt atom located at the active site of MetAP-2 followed by opening of this epoxide by a histidine of the active site, a sequence that leads to irreversible inhibition of MetAP-2.
More recently, a new derivative of fumagillin has been synthesized: fumagalone, in which the epoxide group of fumagillin is replaced with an aldehyde group (Zhou G. et al. J Med Chem., 2003, 46, 3452-3454). Fumagalone exhibits reversible inhibitory activity on the MetAP-2 enzyme in vitro, by reaction of the aldehyde group with histidine 231 of the MetAP-2 enzyme, forming an aminal. Fumagalone also displays inhibitory activity on the proliferation of endothelial cells in vivo.
This model suggests that analogues of fumagalone would be capable of interfering with the enzyme near the active site of MetAP-2. The present applicants used this enzyme for identifying novel fumagalone derivatives and so as to take advantage of better anti-angiogenic candidates for the topical and systemic treatment of disorders that may have a proliferative, inflammatory and/or immunosuppressive component, notably in the field of dermatology.